1. Field of the Invention
This invention relates to small molecule inhibitors of the IgE response to allergens that are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic. This invention also relates to small molecules that are proliferation inhibitors and thus they are useful as anticancer agents.
2. Description of the Related Art
Allergies and Asthma
An estimated 10 million persons in the United States have asthma, about 5% of the population. The estimated cost of asthma in the United States exceeds $6 billion. About 25% of patients with asthma who seek emergency care require hospitalization, and the largest single direct medical expenditure for asthma has been inpatient hospital services (emergency care), at a cost of greater than $1.6 billion. The cost for prescription medications, which increased 54% between 1985 and 1990, was close behind at $1.1 billion (Kelly, Pharmacotherapy 12:13S-21S (1997)).
According to the National Ambulatory Medical Care Survey, asthma accounts for 1% of all ambulatory care visits, and the disease continues to be a significant cause of missed school days in children. Despite improved understanding of the disease process and better drugs, asthma morbidity and mortality continue to rise in this country and worldwide (U.S. Department of Health and Human Services; 1991, publication no. 91-3042). Thus, asthma constitutes a significant public health problem.
The pathophysiologic processes that attend the onset of an asthmatic episode can be broken down into essentially two phases, both marked by bronchoconstriction, that causes wheezing, chest tightness, and dyspnea. The first, early phase asthmatic response is triggered by allergens, irritants, or exercise. Allergens cross-link immunoglobulin E (IgE) molecules bound to receptors on mast cells, causing them to release a number of pre-formed inflammatory mediators, including histamine. Additional triggers include the osmotic changes in airway tissues following exercise or the inhalation of cold, dry air. The second, late phase response that follows is characterized by infiltration of activated eosinophils and other inflammatory cells into airway tissues, epithelial desquamonon, and by the presence of highly viscous mucus within the airways. The damage caused by this inflammatory response leaves the airways xe2x80x9cprimedxe2x80x9d or sensitized, such that-smaller triggers are required to elicit subsequent asthma symptoms.
A number of drugs are available for the palliative treatment of asthma; however, their efficacies vary markedly. Short-acting xcex22-adrenergic agonists, terbutaline and albuterol, long the mainstay of asthma treatment, act primarily during the early phase as bronchodilators. The newer long-acting xcex22-agonists, salmeterol and formoterol, may reduce the bronchoconstrictive component of the late response. However, because the xcex22-agonists do not possess significant antiinflammatory activity, they have no effect on bronchial hyperreactivity.
Numerous other drugs target specific aspects of the early or late asthmatic responses. For example, antihistamines, like loratadine, inhibit early histamine-mediated inflammatory responses. Some of the newer antihistamines, such as azelastine and ketotifen, may have both antiinflammatory and weak bronchodilatory effects, but they currently do not have any established efficacy in asthma treatment. Phosphodiesterase inhibitors, like theophylline/xanthines, may attenuate late inflammatory responses, but there is no evidence that these compounds decrease bronchial hyperreactivity. Anticholinergics, like ipratopium bromide, which are used in cases of acute asthma to inhibit severe bronchoconstriction, have no effect on early or late phase inflammation, no effect on bronchial hyperreactivity, and therefore, essentially no role in chronic therapy.
The corticosteroid drugs, like budesonide, are the most potent antiinflammatory agents. Inflammatory mediator release inhibitors, like cromolyn and nedocromil, act by stabilizing mast cells and thereby inhibiting the late phase inflammatory response to allergen. Thus, cromolyn and nedocromil, as well as the corticosteroids, all reduce bronchial hyperreactivity by minimizing the sensitizing effect of inflammatory damage to the airways. Unfortunately, these antiinflammatory agents do not produce bronchodilation.
Several new agents have been developed that inhibit specific aspects of asthmatic inflammation. For instance, leukotriene receptor antagonists (ICI-204, 219, accolate), specifically inhibit leukotriene-mediated actions. The leukotrienes have been implicated in the production of both airway inflammation and bronchoconstriction.
Thus, while numerous drugs are currently available for the treatment of asthma, these compounds are primarily palliative and/or have significant side effects. Consequently, new therapeutic approaches which target the underlying cause rather than the cascade of symptoms would be highly desirable. Asthma and allergy share a common dependence on IgE-mediated events. Indeed, it is known that excess IgE production is the underlying cause of allergies in general and allergic asthma in particular (Duplantier and Cheng, Ann. Rep. Med. Chem. 29:73-81 (1994)). Thus, compounds that lower IgE levels may be effective in treating the underlying cause of asthma and allergy.
None of the current therapies eliminate the excess circulating IgE. The hypothesis that lowering plasma IgE may reduce the allergic response, was confirmed by recent clinical results with chimeric anti-IgE antibody, CGP-51901, and recombinant humanized monoclonal antibody, rhuMAB-E25. Indeed, three companies, Tanox Biosystems, Inc., Genentech Inc. and Novartis AG are collaborating in the development of a humanized anti-IgE antibody (BioWorld(copyright) Today, Feb. 26, 1997, p. 2) which will treat allergy and asthma by neutralizing excess IgE. Tanox has already successfully tested the anti-IgE antibody, CGP-51901, which reduced the severity and duration of nasal symptoms of allergic rhinitis in a 155-patient Phase II trial (Scrip #2080, Nov 24, 1995, p.26). Genentech recently disclosed positive results from a 536 patient phase-II/III trials of its recombinant humanized monoclonal antibody, rhuMAB-E25 (BioWorld(copyright) Today, Nov. 10, 1998, p. 1). The antibody, rhuMAB-E25, administered by injection (highest dose 300 mg every 2 to 4 weeks as needed) provided a 50% reduction in the number of days a patient required additional xe2x80x9crescuexe2x80x9d medicines (antihistimines and decongestants), compared to placebo. More recently, Dr. Henry Milgrom et. al. of the National Jewish Medical and Research Center in Denver, Colo., published the clinical results of rhuMAB-25 in moderate to severe asthma patients (317 patients for 12 weeks, iv injection every two weeks) and concluded that this drug is xe2x80x9cgoing to be a breakthroughxe2x80x9d (New England Journal of Medicine, Dec. 23, 1999). A Biologics License Application (BLA) for this product has been submitted to the FDA in June, 2000 jointly by Novartis Pharmaceuticals Corporation, Tanox Inc., and Genetech, Inc. The positive results from anti-IgE antibody trials suggest that therapeutic strategies aimed at IgE down-regulation may be effective.
Cancer and Hyperproliferation Disorders
Cellular proliferation is a normal process that is vital to the normal functioning of most biological processes. Cellular proliferation occurs in all living organisms and involves two main processes: nuclear division (mitosis), and cytoplasmic division (cytokinesis). Because organisms are continually growing and replacing cells, cellular proliferation is essential to the vitality of the healthy cell. The disruption of normal cellular proliferation can result in a variety of disorders. For example, hyperproliferation of cells may cause psoriasis, thrombosis, atherosclerosis, coronary heart disease, myocardial infarction, stroke, smooth muscle neoplasms, uterine fibroid or fibroma, and obliterative diseases of vascular grafts and transplanted organs. Abnormal cell proliferation is most commonly associated with tumor formation and cancer.
Cancer is a major disease and is one of the leading causes of mortality both in the United States and internationally. Indeed, cancer is the second leading cause of death in the United States. According to the National Institute of Health, the overall annual cost for cancer is approximately $107 billion, which includes $37 billion for direct medical costs, $11 billion for indirect costs of lost productivity due to illness and $59 billion for indirect costs of lost productivity due to premature death. Not surprisingly, considerable efforts are underway to develop new treatments and preventative measures to combat this devastating illness.
Currently, cancer is primarily treated using a combination of surgery, radiation and chemotherapy. Chemotherapy involves the use of chemical agents to disrupt the replication and metabolism of cancerous cells. Chemotherapeutic agents which are currently being used to treat cancer can be classified into five main groups: natural products and their derivatives; anthacyclines; alkylating agents; antiproliferatives and hormonal agents.
One embodiment of the present invention discloses benzimidazole compounds that modulate IgE and inhibit cell proliferation. Benzimidazole compounds are known in the prior art, for example in European Patent No. 719,765 and U.S. Pat. No. 5,821,258. Both references, however, disclose compounds that contain an active ingredient that acts on DNA, and are structurally different from the benzimidazole derivatives of the current invention. The compounds of the prior art alkylate DNA and there is no suggestion in the references that the disclosed benzimidazole compounds modulate IgE or inhibit the cell proliferation. Further, the compounds described in both references are described as anticancer, antiviral or antimicrobial agents. The anti-allergy or anti-asthma properties of the benzimidazole compounds of the current invention have not previously been recognized. Further, in describing the anticancer properties of benzimidazole compounds, these references disclose chemotherapeutic agents that are DNA alkylating agents. The inhibition of cell proliferation using compounds of the present invention is not disclosed.
The present invention discloses several compounds that are active in down-regulating the IgE response to allergens and other provocative stimuli. One compound disclosed for use in the treatment of a condition associated with an excess IgE level and/or abnormal cell proliferation has a formula: 
wherein R is selected from the group consisting of H, C1-C5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino alkyl, wherein said C1-C5 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl;
wherein R1 and R2 are independently selected from the group consisting of H, alkyl, substituted alkyl, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;
wherein said substituted phenyl, substituted naphthyl and substituted heteroaryl contain 1-3 substituents, wherein said substituent is selected from the group consisting of H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH3, COOH, COORxe2x80x2 CORxe2x80x2, CN, CF3, OCF3, NO2, NRxe2x80x2Rxe2x80x2, NHCORxe2x80x2 and CONRxe2x80x2Rxe2x80x2;
wherein R3 and R4 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl and CORxe2x80x2;
wherein Rxe2x80x2 is selected from the group consisting of H, alkyl, substituted alkyl, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, polycyclic aliphatics, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;
wherein X and Y are independently selected from the group consisting of H, halogens, alkoxy, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH3, COOH, CN, CF3, OCF3, NO2, COORxe2x80x3, CHO and CORxe2x80x3; and
wherein Rxe2x80x3 is a C1-C8 alkyl, wherein said C1-C8 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl.
A compound of the aforementioned genus may contain a polycyclic aliphatic group which is selected from the group consisting of adamantyl, bicycloheptyl, camphoryl, bicyclo[2,2,2]octanyl and norbornyl.
A compound of the aforementioned genus may contain a heteroaryl and a substituted heteroaryl which is selected from the group consisting of pyridines, thiazoles, isothiazoles, oxazoles, pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles, pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines, pyrazoles, imidazoles, indoles, quinolines, iso-quinolines, benzothiophines, benzofurans, parathiazines, pyrans, chromenes, pyrrolidines, pyrazolidines, imidazolidines, morpholines, thiomorpholines, and the corresponding heterocyclics.
Specific compounds of Genus I are also disclosed in accordance with the current invention. These compounds are identified as Compounds I.1 to I.192 and their representative structures are illustrated below.
Another compound for use in the treatment of a condition associated with an excess IgE level and/or abnormal cell proliferation is disclosed in accordance with the present invention. The compound has a formula: 
wherein R is selected from the group consisting of H, C1-C5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino alkyl, wherein said C1-C5 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl;
wherein R1 and R2 are independently selected from the group consisting of H, alkyl, substituted alkyl, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;
wherein said substituted phenyl, substituted naphthyl and substituted heteroaryl contain 1-3 substituents, wherein said substituent is selected from the group consisting of H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH3, COOH, COORxe2x80x2 CORxe2x80x2, CN, CF3, OCF3, NO2, NRxe2x80x2Rxe2x80x2, NHCORxe2x80x2 and CONRxe2x80x2Rxe2x80x2;
wherein R3 and R4 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl and CORxe2x80x2;
wherein Rxe2x80x2 is selected from the group consisting of H, alkyl, substituted alkyl, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, polycyclic aliphatics, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;
wherein X and Y are independently selected from the group consisting of H, halogens, alkoxy, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH3, COOH, CN, CF3, OCF3, NO2, COORxe2x80x3, CHO and CORxe2x80x3; and
wherein Rxe2x80x3 is a C1-C8 alkyl, wherein said C1-C9 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl.
A compound of the aforementioned genus may contain a polycyclic aliphatic group which is selected from the group consisting of adamantyl, bicycloheptyl, camphoryl, bicyclo[2,2,2]octanyl and norbornyl.
A compound of the aforementioned genus may contain a heteroaryl and a substituted heteroaryl which is selected from the group consisting of pyridines, thiazoles, isothiazoles, oxazoles, pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles, pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines, pyrazoles, imidazoles, indoles, quinolines, iso-quinolines, benzothiophines, benzofurans, parathiazines, pyrans, chromenes, pyrrolidines, pyrazolidines, imidazolidines, morpholines, thiomorpholines, and the corresponding heterocyclics.
Specific compounds of Genus II are also disclosed in accordance with the current invention. These compounds are identified as Compounds II.1 to II.90 and their representative structures are illustrated below.
Another compound for use in the treatment of a condition associated with an excess IgE level and/or abnormal cell proliferation is disclosed in accordance with the present invention. The compound has a formula: 
wherein R is selected from the group consisting of H, C1-C5 alkyl, benzyl, p-fluorobenzyl and di-alkylamino alkyl, wherein said C1-C5 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl;
wherein R1 and R2 are independently selected from the group consisting of H, alkyl, substituted alkyl, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, polycyclic aliphatic groups, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;
wherein said substituted phenyl, substituted naphthyl and substituted heteroaryl contain 1-3 substituents, wherein said substituent is selected from the group consisting of H, halogens, polyhalogens, alkoxy group, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH3, COOH, COORxe2x80x2 CORxe2x80x2, CN, CF3, OCF3, NO2, NRxe2x80x2Rxe2x80x2, NHCORxe2x80x2 and CONRxe2x80x2Rxe2x80x2;
wherein R3 and R4 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl and CORxe2x80x2;
wherein Rxe2x80x2 is selected from the group consisting of H, alkyl, substituted alkyl, C3-C9 cycloalkyl, substituted C3-C9 cycloalkyl, polycyclic aliphatics, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl, wherein said heteroaryl and said substituted heteroaryl contain 1-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur;
wherein X and Y are independently selected from the group consisting of H, halogens, alkoxy, substituted alkoxy, alkyl, substituted alkyl, dialkylaminoalkyl, hydroxyalkyl, OH, OCH3, COOH, CN, CF3, OCF3, NO2, COORxe2x80x3, CHO and CORxe2x80x3; and
wherein Rxe2x80x3 is a C1-C8 alkyl, wherein said C1-C8 alkyl is selected from the group consisting of a straight chain, branched or cyclic alkyl.
A compound of the aforementioned genus may contain a polycyclic aliphatic group which is selected from the group consisting of adamantyl, bicycloheptyl, camphoryl, bicyclo[2,2,2]octanyl and norbornyl.
A compound of the aforementioned genus may contain a heteroaryl and a substituted heteroaryl which is selected from the group consisting of pyridines, thiazoles, isothiazoles, oxazoles, pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles, pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines, pyrazoles, imidazoles, indoles, quinolines, iso-quinolines, benzothiophines, benzofurans, parathiazines, pyrans, chromenes, pyrrolidines, pyrazolidines, imidazolidines, morpholines, thiomorpholines, and the corresponding heterocyclics.
Specific compounds of Genus III are also disclosed in accordance with the current invention. These compounds are identified as Compounds III.1 to III.154 and their representative structures are illustrated below.
For each chemical structure disclosed herein, the hydrogen atoms on the heteroatoms have been omitted for clarity purposes. Where open valences on heteroatoms are indicated, it is assumed that these valences are filled by hydrogen atoms.
A method for treating a disease condition associated with excess IgE and/or abnormal cell proliferation (i.e. cancer) in a mammal is also disclosed. In one aspect, the method comprises the step of administering to the mammal an IgE-suppressing amount or anti-cell proliferation amount of a pharmaceutical formulation comprising at least one benzimidazole compound from the above-disclosed small molecule families.
In accordance with a variation of the method of treatment, the small molecule IgE-suppressing compound may be administered in conjunction with at least one additional agent, which is active in reducing a symptom associated with an allergic reaction. In one embodiment, the small molecule inhibitor may be mixed with at least one additional active ingredient to form a pharmaceutical composition. Alternatively, the small molecule inhibitor may be co-administered at the same time or according to different treatment regimens with the at least one additional active agent.
The at least one additional active ingredient may be a short-acting xcex22-adrenergic agonist selected from the group consisting of terbutaline and albuterol; a long-acting xcex22-adrenergic agonist selected from the group consisting of salmeterol and formoterol; an antihistamine selected from the group consisting of loratadine, azelastine and ketotifen; a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor or a leukotriene receptor antagonist.
In another embodiment, the benzimidazole compound may be administered in conjunction with at least one additional active agent. These active agents include antifungals, antivirals, antibiotics, anti-inflammatories, and anticancer agents. Anticancer agents include, but are not limited to, alkylating agents (lomustine, carmustine, streptozocin, mechlorethamine, melphalan, uracil nitrogen mustard, chlorambucil cyclophosphamide, iphosphamide, cisplatin, carboplatin mitomycin thiotepa dacarbazine procarbazine, hexamethyl melamine, triethylene melamine, busulfan, pipobroman, and mitotane); antimetabolites (methotrexate, trimetrexate pentostatin, cytarabine, ara-CMP, fludarabine phosphate, hydroxyurea, fluorouracil, floxuridine, chlorodeoxyadenosine, gemcitabine, thioguanine, and 6-mercaptopurine); DNA cutters (bleomycin); topoisomerase I poisons (topotecan irinotecan and camptothecin); topoisomerase II poisons (daunorubicin, doxorubicin, idarubicin, mitoxantrone, teniposide, and etoposide); DNA binders (dactinomycin, and mithramycin); and spindle poisons (vinblastine, vincristine, navelbine, paclitaxel, and docetaxel).
In another embodiment, the benzimidazole compounds of the current invention are administered in conjunction with one or more other therapies. These therapies include, but are not limited to radiation, immunotherapy, gene therapy and surgery. These combination therapies may be administered simultaneously or sequentially. For example, radiation may be administered along with the administration of benzimidazole compounds, or may be administered at any time before or after administration of benzimidazole compounds.
A dose of about 0.01 mg to about 100 mg per kg body weight per day of the small molecule IgE inhibitory compound is preferably administered in divided doses daily.
A method for treating a disease condition associated with excess IgE or abnormal cell proliferation in a mammal is also disclosed which comprises the step of administering to the mammal an therapeutic amount of a pharmaceutical formulation comprising at least one compound selected from Genus I, Genus II and/or Genus III.
The methods provided herein for treating diseases and processes mediated by undesired, uncontrolled or abnormal cell proliferation, such as cancer, involve administering to a mammal a composition of the benzimidazole compounds disclosed herein to inhibit cell proliferation. The method is particularly useful for preventing or treating tumor formation and progresson. In one embodiment of the invention, the compounds and methods disclosed are especially useful in treating estrogen receptor positive and estrogen receptor negative type breast cancers.
Other variations within the scope of the present invention may be more fully understood with reference to the following detailed description.